Melphalan (Intravenous)

Melphalan is an alkylating agent that can be effective in the treatment of certain neoplastic diseases by interfering with the replication of cells in those areas affected by the disease.

Overview

Melphalan has been approved for use in the treatment of certain forms of cancer since the early 1960's. It is a phenylalanine derivative of nitrogen mustard. All medications in this cluster of drugs act as alkylating agents which are active against the cells of a tumor. It does this by inhibiting the growth of cells by interfering with the DNA and RNA of these cells. It is important to note that melphalan and other similar medications do not cure the patient of cancer. These medications only mediate the disease by inhibiting the growth of tumors and cancer cells.

Melphalan has a cytotoxic effect on the body that accumulates over time. Patients generally take the drug for a few weeks and then discontinue its use for a few weeks until blood counts recover enough to reintroduce the medication. Protracted use of melphalan has been known to cause the development of secondary cancers in patients including carcinomas and some forms of leukemia.

Melphalan is a powerful medication that can cause a host of side effects. Patients with a weak immune system or kidney or liver impairment need to take this medication with great caution. All patients who are prescribed melphalan should do so under medical supervision that involves frequent blood tests and monitoring of platelets and white blood cells to ensure that those patients can fight infection. Patients taking melphalan should avoid exposure to people who are sick as this drug limits their ability to fight infection. This drug may also cause nausea, vomiting and diarrhea. It may impact fertility and can cause amenorrhea in premenopausal women.

Melphalan may be taken as an injection or in tablet form. It is more common as an injection in the treatment of multiple myeloma. For patients with ovarian cancer, the recommended treatment form is tablets taken orally.

Women who are pregnant should not take this medication.

Conditions Treated

Type Of Medication

  • Phenylalanine derived from a nitrogen mustard
  • Alkylating agent

Side Effects

As with any strong and effective medication, melphalan can and often does cause side effects in patients. Some side effects may require medical attention and intervention. Additionally, some of the possible side effects carry significant risk including death.

Possible side effects include:

  • Heart arrhythmia; irregular heartbeat
  • Black stool
  • Shortness of breath
  • Fever
  • Sudden onset rash, red skin
  • Difficulty breathing
  • Bloody stools
  • Bloody urine
  • Chills
  • Painful urination
  • Hoarseness
  • Persistent dry cough
  • Pain in the lower back
  • Unusual or excessive bleeding
  • Bruising easily
  • Edema of the lower legs or feet
  • Pain in the extremities
  • Sore muscles
  • Nausea
  • Diarrhea
  • Mouth sores
  • Pain in the joints
  • Difficulty swallowing
  • Unusual vomiting
  • Nausea and vomiting

Because of its mechanism of action, chemotherapy treatment using melphalan can cause the onset of other medical conditions, some of which are quite serious with significant impact on other systems of the body. These conditions include:

  • Suppression of bone marrow and the development of anemia. This condition can be reversed once therapy is completed.
  • Hemolytic anemia
  • Leukemogenesis, particularly if the chemotherapy regimen is extended over a protracted period of time as this increases toxicity.
  • Myeloproliferative syndrome
  • Acute nonlymphocytic leukemia
  • Chromosome damage
  • Carcinoma
  • Testicular suppression, reversible
  • Testicular suppression, irreversible
  • Suppression of ovarian function that often results in amenorrhea (pre-menopausal)
  • Interstitial pneumonitis
  • Pulmonary fibrosis, possibly with fatal outcome
  • Alopecia
  • Hypersensitivity of the skin
  • Maculopapular rashes
  • Elevated levels of blood urea, particularly in patients with preexisting renal impairment
  • Antidiuretic hormone secretions
  • Vasculitis
  • Cardiac arrest, possibly with fatal outcome

Dosage

Melphalen is administered through two different platforms. It may be administered intravenously or patients may take the medication daily via tablets taken orally.

For treatment of multiple myeloma, the usual intravenous dosage level is 16mg/m2. It is given in a single infusion that takes roughly 20 minutes. Infusions are given every two weeks for a total of four doses. The patient must then recover from the toxicity of the medication. This period varies depending on the patient and the results of blood testing. Once the patient has recovered adequately, infusions are restarted and administered every four weeks until such time as tests show desired results or it is determined that the medication is not effective in treating the disease.

If the treatment is delivered orally, the conventional dosage level is a 6mg tablet taken once daily. This treatment continues for two or three weeks. After three weeks, the patient should stop taking the medication for as long as four weeks with close monitoring of white blood cell counts as well as platelets. If the counts look good, the patient should resume taking the medication at a dose of 2mg daily.

There has been research into other dosing levels of melphalan with varying degrees of success. These include adjusting the maintenance dose upward with caution to maximize the therapeutic effects of the drug. There has also been some experimentation with beginning dosages at 10 mg daily for up to 10 days. There have also been studies piloting lower dosing levels for longer periods of time. There is some evidence that melphalan is more effective and patients are better able to tolerate it for longer periods of time when it is taken in conjunction with prednisone. In all cases, melphalan proves effective for one third to one-half of all patients that take it.

When melphalan is used in the treatment of ovarian cancer, only the oral route is suggested. The usual dosing level is 0.2 mg/kg taken orally for five days. This regimen is followed at four to five week intervals based on the patient's ability to tolerate it and the efficacy of the medication in the treatment of the condition in that individual patient.

For patients who suffer from renal impairment, there is no evidence to suggest that an oral dosing level should be reduced. For patients who are given the intravenous form of the medication, there is a tentative recommendation to reduce the initial dose by 50%.

Blood cell counts should be monitored on a weekly basis. Treatment should be discontinued if the patient's white blood cell count registers at less than 3000/mm3.

Interactions

Melphalan interacts with many families of medications, interfering with their effectiveness. These medications may also impact the effect of the melphalan. Melphalan interacts with 185 different drugs to a greater or lesser degree.

Major drug interactions include:

  • Adalimumab
  • Clozapine
  • Deferiprone
  • Bcg
  • Fingolimod
  • Certolizumab
  • Etanercept
  • Infliximab
  • Golimumab
  • Vaccine, Influenza virus, trivalent, live
  • Vaccine, influenza virus, live, h1n1
  • Leflunomide
  • Vaccine, measles virus
  • Vaccine, mumps vaccine
  • Vaccine, measles, mumps, rubella (MMR)
  • Vaccine, varicella virus
  • Natalizumab
  • Nalidixic acid
  • Vaccine, poliovirus, trivalent, live
  • Vaccine, smallpox
  • Vaccine, rotavirus
  • Vaccine, rubella virus
  • Talimogene laherparepvec
  • Samarium sm 153 lexidronam
  • Thalidomide
  • Tofacitinib
  • Teriflunomide
  • Thiotepa
  • Vaccine, typhoid, live
  • Vaccine, Zoster virus, live
  • Vaccine, Yellow fever

Melphalan has moderate interactivity levels with the following medications:

  • Aldesleukin
  • Vaccine, adenovirus
  • Anakinra
  • Alefacept
  • Amphotericin b, cholesteryl sulfate
  • Alemtuzumab
  • Vaccine, anthrax, absorbed
  • Amphotericin b, lipid complex
  • Azathioprine
  • Bleomycin
  • Busulfan
  • Bendamustine
  • Canakinumab
  • Cytarabine liposomal
  • Candida albicans extract
  • Cyclosporine
  • Capecitabine
  • Cyclophosphamide
  • Carboplatin
  • Coccidiodin skin test
  • Carmustine
  • Clofarabine
  • Vaccine, cholera, live
  • Cisplatin
  • Vaccine, cholera
  • Daunorubicin liposomal
  • Dacarbazine
  • Docetaxel
  • Dactinomycin
  • Tetanus toxoid
  • Daunorubicin
  • Diphtheria toxoid
  • Decitabine
  • Pertussis, whole cell
  • Denosumab
  • Pertussis, acellular
  • Vaccine, Haemophilus b conjugate (hboc)
  • Etoposide
  • Efalizumab
  • Filgrastim
  • Fludarabine
  • Fluorouracil
  • Floxuridine
  • Gemcitabine
  • Ganciclovir
  • Vaccine, haemophilus b conjugate (prp-omp)
  • Vaccine, hepatitis a, adult
  • Vaccine, hepatitis b, pediatric
  • Vaccine, hepatitis a, pediatric
  • Vaccine, hepatitis b, adult
  • Hydroxyurea
  • Vaccine, human papillomavirus
  • Histoplasmin
  • Imatinib
  • Idarubicin
  • Interferon alfa-2a
  • Ifosfamide
  • Interferon alfa-2b
  • Vaccine, influenza virus, inactivated, h1n1
  • Ribavirin
  • Vaccine, influenza virus, h5n1
  • Mesna
  • Vaccine, influenza virus, inactivated
  • Vaccine, Japanese encephalitis virus, nakayama
  • Vaccine, japanese enceph, inactivated, sa14-14-2
  • Vaccine, lyme disease
  • Lomustine
  • Vaccine, meningococcal conjugate
  • Mechlorethamine
  • Mumps skin test antigen
  • Vaccine, meningococcal group B
  • Vaccine, mixed respiratory
  • Mercaptopurine
  • Mitoxantrone
  • Vaccine, meningococcal polysaccharide
  • Mitomycin
  • Methotrexate
  • Niraparib
  • Nelarabine
  • Olaparib
  • Oxaliplatin
  • Ocrelizumab
  • Omacetaxine
  • Palifermin
  • Vaccine, poliovirus, inactivated
  • Pegfligrastim
  • Vaccine, pneumococcal 7-valent
  • Pemetrexed
  • Vaccine, pneumococcal 23-polyvalent
  • Pentostatin
  • Vaccine, pneumococcal 13-valent
  • Vaccine, plague
  • Vaccine, rabies, human diploid cell
  • Ruxolitinib
  • Vaccine, rabies, purified chicken embryo cell
  • Roflumilast
  • Rilonacept
  • Radium 223 dichloride
  • Sargramostim
  • Strontium-89 chloride
  • Sipuleucel T
  • Sodium phosphate p32
  • Streptozocin
  • Multiple skin test antigens
  • Staphage lysate (spl)
  • Tbo-fligrastim
  • Vaccine, typhoid, inactivated
  • Temozolomide
  • Tuberculin purified protein derivative
  • Thioguanine
  • Trichophyton skin test
  • Topotecan
  • Vinorelbine
  • Valganciclovir
  • Vitamin E
  • Vaccine, zoster inactivated

Melphalan also has modest interaction with the following medications. While these medicines can possibly be taken concomitantly with melphalan, the prescribing physician should certainly be aware of their use.

  • Azithromycin
  • Cimetidine
  • Bortezomib
  • Cinoxacin
  • Ciprofloxacin
  • Doxorubicin
  • Enoxacin
  • Trovafloxacin
  • Delafloxacin
  • Epirubicin
  • Gemifloxacin
  • Gatifloxacin
  • Grepafloxacin
  • Lomefloxacin
  • Levofloxacin
  • Moxifloxacin
  • Ofloxacin
  • Sparfloxacin
  • Norfloxacin
  • Trovafloxacin

Warnings

Allergic reaction and anaphylaxis are possible with melphalan. Allergic reactions should be treated based on the symptoms the patient manifests. Patients who have demonstrated hypersensitivity to melphalan or other similar medications should not be prescribed melphalan.

When given by injection intravenously, melphalan may cause tissue damage around the vein. It is generally recommended to deliver the medication via an injection port to avoid damage and injury.

One of the major risks of melphalan is bone marrow suppression and conditions that may result from that suppression including leukopenia, anemia, or thrombocytopenia. When a patient is undergoing treatment with melphalan, frequent monitoring of platelets, white blood cell counts and hemoglobin is indicated. Dosing and intervals away from medication should be adjusted based on the results of those tests.

Melphalan is considered a Category D drug for pregnancy, meaning that it is contraindicated for women who are pregnant. This medication has been shown to cause damage to the fetus in rats. Including brain development, vision, as well as other hazards to the baby. Conclusive studies in humans have not been conducted but the animal studies are conclusive enough to rate this drug as Category D.

Melphalan may impair fertility in both men and women. Its use may result in suppression of both ovarian and testicular function.

Use of melphalan can result in the development of secondary malignancies. The exact risk is not known, but patients run the risk of developing several cancers of the blood, particularly if they take melphalan over a protracted period of time as the risk is tied to an accumulation of dose. Physicians and patients must weigh the potential benefits of melphalan therapy versus those potential risks.

Use of melphalan has been linked to both chromosome and chromatid damage in humans as well as rats.

Patients who suffer from certain infectious diseases that may be viral, fungal, bacterial or protozoal should use melphalan with great caution. As with any antineoplastic drug, melphalan suppresses bone marrow which can reduce a patient's ability to fight infection. Its use may be contraindicated for these patients as it may worsen their level of infection and their ability to fight against it.

Melphalan should only be administered by doctors and health care workers who are qualified and have experience with chemotherapy medications.

There have been reported cases of severe renal failure when melphalan is given as an injection followed by doses of cyclosporine or cisplatin. This should be avoided.

Because it is not known if melphalan passes through breast milk, nursing mothers should not take this drug.

All doctors and healthcare workers who handle melphalan should do so with caution as it may cause an adverse reaction. Gloves should always be worn when handling this medication.

An overdose of melphalan can be fatal. An overdose may also cause severe colitis, diarrhea and other digestive symptoms including internal bleeding in the digestive tract. It may result in loss of consciousness. Patients should follow dosing instructions with fidelity. They should not take more of the medicine or take it for a longer period of time than is prescribed. The medication must be stored in a secure location where no one would accidentally take it.

Patients being treated with melphalan should not be administered vaccines. Close medical supervision of the patient is required of anyone taking melphalan.

Storage

In its intravenous form, melphalan is sold in glass vials with freeze-dried powder. This substance should be stored at room temperature (68 to 77 degrees Fahrenheit) in a dry dark location that is safe and secure.

Once it has been reconstituted into the solution for the IV dose, it should be used as quickly as possible as the injection is unstable and begins breaking down after the first 30 minutes.

In tablet form, melphalan comes in containers of 50 tablets. These tablets should be kept refrigerated between 36 and 46 degrees Fahrenheit where it is not exposed to direct light. The medication should also be kept secure and away from children and animals.

Summary

Melphalan is a chemotherapy drug that is used primarily in the treatment of multiple myeloma and ovarian cancers. It is derived from nitrogen mustard and acts as an alkylating agent that disrupts the DNA and RNA of cancer cells and inhibits their growth. It may also act as a bone marrow suppressor which can negatively impact the patient's immune system and make him or her more susceptible to other infections. Patients who have a preexisting infectious condition should avoid taking melphalan. Pregnant women should not take this medication, nor should nursing mothers.

This drug causes many side effects, including flu-like symptoms such as nausea, fever and chills. It can cause other more serious conditions such as secondary cancers that develop because of the cytotoxic effects of this drug. Close and frequent medical supervision is critical for patients who are taking melphalan as part of their cancer treatment. Its possible benefits must be weighed against serious and real risks.

Melphalan does not cure cancer. Its impact is in inhibiting the growth of cancer cells which prevents tumors from getting larger or the cancer from spreading to other parts of the body. It may be given to the patient as an intravenous injection or as a tablet to be taken once a day for the prescribed period of time. Patients will take the medication for a few weeks and then stop its use to allow white blood cell counts to recover and prevent the accumulation of toxicity in the bone marrow of the patient.